Follicle stimulating hormone (FSH) and luteinizing hormone (LH), sometimes referred to as gonadotropins or gonadotropic hormones, are released by the pituitary gland which is attached by a stalk to the hypothalamus.
Hormone release by the anterior lobe of the pituitary gland usually requires prior release of hormones produced by the hypothalamus, such as the GnRH decapeptide.
The administration of GnRH analogs that are antagonistic to the normal function of GnRH has been used to suppress secretion of gonadotropins generally in mammals and to suppress or delay ovulation.
The search for improved GnRH antagonists has resulted in the making of Antide, i.e. [Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3, Lys(Nic).sup.5, D-Lys(Nic).sup.6, ILys.sup.8, D-Ala.sup.10 ]-GnRH; and Cetrorelix, i.e. [Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3, D-Cit.sup.6, D-Ala.sup.10 ]-GnRH. U.S. Pat. No. 5,516,887 describes GnRH antagonists which are said to be more effective than Antide in suppressing plasma testosterone, e.g.[Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3, D-N.sup..epsilon. -carbamoyl Lys.sup.6, Ilys.sup.8, D-Ala.sup.10 ]-GnRH, which is referred to as Antarelix.
U.S. Pat. No. 5,296,468, issued Mar. 22, 1994, discloses the design and synthesis of a number of GnRH antagonists wherein the side chains of selected residues are reacted to create cyanoguanidino moieties, some of which subsequently spontaneously convert to a desired heterocycle, e.g. a 3-amino-1,2,4-triazole(atz). Such cyanoguanidino moieties are built upon the omega-amino group in an amino acid side chain, such as lysine, ornithine, 4-amino phenylalanine (4Aph) or an extended chain version thereof, such as 4-amino homophenylalanine (4Ahp). GnRH antagonists having such significantly modified or unnatural amino acids in the 5- and 6-positions exhibit good biological potency, and those built upon Aph are generally considered to be preferred. One that is especially preferred is Azaline B, i.e. [Ac-D-2Nal.sup.1, D-4ClPhe.sup.2, D-3Pal.sup.3, 4Aph(atz).sup.5, D-4Aph(atz).sup.6, ILys.sup.8, D-Ala.sup.10 ]-GnRH. U.S. Pat. No. 5,506,207 discloses biopotent GnRH antagonists wherein amino-substituted phenylalanine side chains of residues in the 5- and 6-positions are acylated; one particularly potent decapeptide is Acyline, i.e. [Ac-D-2 Nal.sup.1, D-4CiPhe.sup.2, D-3Pal.sup.3, 4Aph(Ac).sup.5, D-4Aph(Ac).sup.6, ILys.sup.8, D-Ala.sup.10 ]-GnRH.
Despite the attractive properties of this group of GnRH antagonists, the search has continued for still further improved GnRH antagonists, particularly those which exhibit long duration of biological action. It can frequently be important that a peptide analog should exhibit a long duration of activity with respect to LH secretion, a property which may be enhanced by the peptide's resistance to proteolytic enzyme degradation in the body for both short-term and long-term treatment indications. In addition, to facilitate administration of these compounds to mammals, particularly humans, without significant gelling, it is considered extremely advantageous for such GnRH antagonistic decapeptides to have high solubility in water at normal physiologic pH, i.e. about pH 5 to about pH 7.4.